In the present study, we performed immunohistochemical studies to investigate the changes of phosphorylated extracellular signal-regulated kinases (pERK) in the central nervous system of SOD1(G93A) transgenic mice. In symptomatic transgenic mice, pERK-immunoreactive astrocytes were detected in the spinal cord, brainstem, central gray and cerebellar nuclei. In contrast to symptomatic mice, no pERK-immunoreactive astrocytes were observed in any brain region of wtSOD1 and presymptomatic mice, and the number and intensity of stained neurons were not different at the age of 8 weeks and 13 weeks. Interestingly, region-specific alterations in pERK immunoreactivity were observed in the hippocampal region and cerebellum. These results provide the first evidence that pERK-immunoreactive astrocytes were found in the CNS of SOD1(G93A) transgenic mice after clinical symptoms, showing a possible consequence of the pathological process of ALS. This study has also demonstrated that pERK increases in the hippocampus and cerebellum, suggesting a role of pERK in an abnormality of cognitive and/or motor function in ALS, respectively. However, the mechanisms underlying the increased immunoreactivity for pERK and the functional implications require elucidation.